At least 20%, perhaps as much as one-third, of colorectal cancer is attributable to inherited factors. Identifying genetic variants is important to elucidate underlying mechanisms of colorectal cancer, the second leading cause of cancer death in the US. First results from genome-wide association studies (GWAS) have demonstrated considerable success in identifying genetic variants associated with various common complex diseases, including colorectal cancer. Given the overall weak associations, large sample sizes, both for the initial genome- wide scan, as well as for the replication in independent study populations, have become crucial in identifying and establishing true associations. To accelerate the discovery of colorectal cancer-related variants, we have formed the Colorectal Cancer GWAS Consortium. The goal of this Consortium is to conduct a pooled analysis of all five existing colorectal cancer GWAS and validate findings from this pooled analysis in a large-scale replication study (specific aim 1). As a first step, we will conduct a combined pooled analysis of five GWAS, including more than 6,500 colorectal cancer cases and more than 9,000 controls. This initial analysis will provide a powerful means to select the most promising genetic variants, which will be followed up in an independent replication study. For this replication study, the Consortium provides about 8,500 colorectal cancer cases and about 11,500 matched controls from eleven well described and mostly prospective study populations, which are protected against recall and survival bias. We will genotype 7,600 variants in the replication study to minimize the number of false- negative findings. Based on recent results of other common complex diseases, we expect to identify several highly significant novel colorectal cancer susceptibility genes/loci. To establish the identity of the underlying causal variants in these true genetic regions, we will further sequence these regions and subsequently genotype newly identified genetic markers in the entire replication study (specific aim 2). As this consortium brings together experts from multiple disciplines, we are well placed to explore fully this unique data set with its detailed exposure assessment and also to investigate potentially important interactions between genetic variants and environmental factors (specific aim 3). This Consortium provides an unprecedented opportunity to investigate the underlying genetic susceptibility to colorectal cancer, which is, at this point, largely unexplained. The large sample size and detailed exposure and outcome ascertainment in the study populations provide a unique resource to conduct a well-powered replication to identify several new CRC susceptibility genes/loci, which could be missed if groups pursued this research individually. We expect that our findings will enhance our understanding of the genetic susceptibility and molecular mechanisms of colorectal carcinogenesis, thus leading to improved preventive strategies. PUBLIC HEALTH RELEVANCE: This large collaborative effort will investigate comprehensively whether common variations in genes influence colorectal cancer risk in humans. Furthermore, the study will examine whether environmental factors, including smoking, medications, alcohol, physical activity, or diet change the risk of colorectal cancer related to these genetic variants. Findings from this study will improve our understanding of how genes and environment modify risk of colorectal cancer, leading to better strategies to prevent this serious disease and to detect it early when it does occur.